Pharmaceutical composition for topical application

ABSTRACT

A pharmaceutical composition comprises a solution having a pH of from 5 to 7.5, including loratadine and/or desloratadine. The composition is suitable for treatment of e.g. allergic rhinitis and allergic conjunctivitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending applicationSer. No. 13/578,425, filed Sep. 23, 2013; which is a National StageApplication of International Application Number PCT/IB2009/055140, filedNov. 18, 2009; which claims priority to European Application No.0821298.7, filed Nov. 21, 2008; all of which are incorporated herein byreference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a pharmaceutical composition for topicalapplication. In particular, the present invention concerns apharmaceutical composition which is suitable for nasal mucosaadministration.

Aqueous pharmaceutical compositions for nasal administration comprisingsolutions of loratadine are disclosed in WO-A-04082589 and solutions ofloratadine and desloratadineare disclosed in WO-A-03101434. The nasalpharmaceutical compositions disclosed in these prior art referencescomprise relatively low levels of antihistamine in solution.

It is an object of the present invention to provide nasal pharmaceuticalcompositions which may comprise relatively higher amounts ofantihistamine in solution than the prior art solutions but which do notdemonstrate increased mucosa irritation.

In accordance with the present invention, there is provided apharmaceutical composition comprising an aqueous solution having a pH offrom 5 to 7.5, preferably from 5 to 7, comprising:

Amount Component (wt %) Example a) At least one 0.02-0.1  antihistamineselected from Loratadine and Desloratadine and their pharmaceuticallyacceptable salts b) At least one  5.0-15.0 PEG 200, PEG 300,polyethylene glycol PEG 400, PEG 600: with a molecular PEG 400 ispreferred weight of from 100 to 600 g/mole (co-solvent) c) Propyleneglycol  5.0-15.0 (co-solvent) d) At least one non-ionic  1.0-10.0 LutrolF127-(non- ethylene oxide/ ionic EO/PO block propylene oxide copolymerwith (EO/PO) block Mw of about copolymer with weight 12,500) averagemolecular weight (Mw) from 10,000 to 15,000 (solubilizer) e)polyoxyethylene 0.5-5.0 Tween 20, Tween 80: (20) sorbitan Tween 80monolaurate and/or (polyoxyethylene polyoxyethylene (20) sorbitan (20)sorbitan monooleate) monooleate (solubilizer) is preferred f) Stabilizerfor 0.05-0.5 Salts of EDTA, antihistamine, salts and esters ofpreferably a gallic acid, chelator stabilizer salts and esters ofascorbic acid, salts of metabisulfite, cysteine and derivatives thereof:Stabilizers which are chelators for the antihistamine are preferred.Alkali salts are preferred e.g. Na₂ EDTA Other optional additives <20Sorbitol, glycerine Water balance to 100.0% Lutrol is a trademark ofBASF SE. Tween is a trademark of Uniquema Americas LLC.

In one embodiment of the present invention, the pharmaceuticalcomposition comprises an aqueous solution having a pH from 5 to 7.5comprising:

Component Amount (wt %) Example Loratadine or a 0.02-0.1 pharmaceutically acceptable salt thereof At least one polyethylene 5.0-15.0 PEG 200, PEG 300, glycol with a molecular PEG 400, PEG 600weight of from 100 to 600 g/mole (co-solvent) Propylene glycol (co- 5.0-15.0 solvent) At least one non-ionic  1.0-10.0 Lutrol F127-Mw12,500 EO/PO block copolymer with weight average molecular weight (Mw)from 10,000 to 15,000 (solubilizer) polyoxyethylene (20) 0.5-5.0 Tween20, Tween 80, sorbitan monolaurate and/or polyoxyethylene (20) sorbitanmonooleate (solubilizer) Stabilizer 0.05-0.5  Salts of EDTA, salts andesters of gallic acid, salts and esters of ascorbic acid, salts ofmetabisulfite, cysteine and derivatives thereof Other optional additives<20 Sorbitol, glycerine Water balance to 100.0%

A particularly preferred pharmaceutical composition of this embodimentcomprises an aqueous solution having a pH from 5 to 7 comprising:

Component Amount (wt %) Loratadine or salt thereof 0.06 PEG 400 10.0Propylene glycol 10.0 At least one non-ionic EO/PO 5.0 block copolymerwith weight average molecular weight (Mw) of about 12,500 Polysorbate 801.8 Na₂EDTA 0.1 Water balance to 100.0%

In another embodiment of the present invention, the pharmaceuticalcomposition comprises an aqueous solution having a pH from 5 to 7.5comprising:

Component Amount (wt %) Example Desloratadine or a 0.02-0.1 pharmaceutically acceptable salt thereof At least one polyethylene 5.0-15.0 PEG 200, PEG 300, glycol with a molecular PEG 400, PEG 600weight of from 100 to 600 g/mole (co-solvent) Propylene glycol  5.0-15.0(co-solvent) At least one non-ionic  1.0-10.0 Lutrol F127-Mw 12,500EO/PO block copolymer with weight average molecular weight (Mw) from10,000 to 15,000 (solubilizer) polyoxyethylene (20) 0.5-5.0 Tween 20,Tween 80, sorbitan monolaurate and/or polyoxyethylene (20) sorbitanmonooleate (solubilizer) Stabilizer 0.05-0.5  Salts of EDTA, salts andesters of gallic acid, salts and esters of ascorbic acid, salts ofmetabisulfite, cysteine and derivatives thereof Other optional additives<20 Sorbitol, glycerine Water balance to 100.0%

A particularly preferred pharmaceutical composition of this embodimentcomprises an aqueous solution having a pH from 5 to 7 comprising:

Component Amount (wt %) Desloratadine or salt thereof 0.06 PEG 400 10.0Propylene glycol 10.0 At least one non-ionic EO/PO 5.0 block copolymerwith weight average molecular weight (Mw) 12,500 Polysorbate 80 1.8Na₂EDTA 0.1 Water balance to 100.0%

In comparison to the prior art formulations, by using a combination ofthe four components b), c), d) and e), pharmaceutical compositions ofthe present invention contain higher dosage levels of antihistamine insolution but overall lower dosages of potential irritants. For example,if component b) was eliminated, higher levels of component c) would berequired to solubilise the antihistamine, and visa-versa: higher levelsof b) or c) on their own in the composition causes irritation on thenasal mucosa, which in turn leads to a reduction the time thecomposition may be effective. Similarly, if component d) was eliminated,higher levels of component e) would be required to solubilise theantihistamine, and visa-versa: higher levels of d) or e) on their own inthe composition causes irritation on the nasal mucosa, which in turnleads to a reduction the time the composition may be effective.

The pharmaceutical composition of the present invention may contain, inaddition to co-solvents b) and c), one or more other co-solvents, suchas sorbitol and glycerine, but such co-solvents should be used atnon-irritating levels.

The pharmaceutical composition of the present invention may contain, inaddition to co-solubilizers b) and c), one or more otherco-solubilizers, but such co-solubilizers should be used atnon-irritating levels.

The stabilizer is preferably a chelator for the antihistamine.

The aqueous solution may require pH adjustment to the range 5 to 7.5,preferably 5 to 7. This can be achieved readily by a person skilled inthe art. For example, if the pH of the solution is lower than 5, thenthe pH may be raised by the incorporation of an appropriate amount ofalkali, such as NaOH solution.

The pharmaceutical composition is especially suitable for nasaladministration, for example for the treatment of allergic rhinitis,though it may also be suitable for ocular administration, for examplefor the relief of allergic conjunctivitis.

The invention in its various embodiments shall now be further describedby way of exemplification only:

A pharmaceutical composition according to the present invention wasprepared as follows:

10.0 parts by wt PG (Propylene Glycol) and 10.0 parts by wt PEG₄₀₀(Macrogol 400) are mixed. The amount of 0.06 parts by wt Loratadine isdissolved in the obtained mixture to obtain Solution A.

Separately, 5.0 parts by wt Lutrol F127 (Poloxamer 407), 1.8 parts by wtTween 80 (Polysorbate 80) and 0.1 parts by wt Na.sub.2EDTA are dissolvedin 70 parts by wt purified water, preheated to 60° C., to obtainSolution B.

Solution A is added to Solution B at constant stirring to obtainSolution C.

Solution C is adjusted as necessary to pH 5.5 with 1M solution of SodiumHydroxide and is complemented to a total of 100 parts w/w with purifiedwater to obtain the final composition.

The composition is as shown in Table 1.

TABLE 1 Component Amount (wt %) Loratadine 0.06 active drug PEG400 10.0co-solvent PG 10.0 co-solvent Lutrol F127 5.0 solubilizer Tween 80 1.8solubilizer EDTA 0.1 stabilizer (chelator) Water balance to 100.0% —

The pharmaceutical composition has the characteristics shown in Table 2:

TABLE 2 Appearance clear, colorless pH 5.5 Density at 20° C. p_(s) =1.0273 at 25° C. p_(s) = 1.0251 Dynamic viscosity 11, at 20° C. η =54.57 · ( 2.4100 − 1.0273 ) · mPa · s 0.07752 = 5.84 at 25° C. η = 45.93· ( 2.4100 − 1.0251 ) · 0.07752 = 4.93 Loratadine content 0.06 Na₂EDTAcontent 0.1

We claim:
 1. A pharmaceutical composition comprising an aqueous solutionhaving a pH of from 5 to 7.5 comprising: Component Amount (wt %) a) Atleast one antihistamine selected 0.02-0.1  from Loratadine andDesloratadine and their pharmaceutically acceptable salts b) At leastone polyethylene glycol with  5.0-15.0 a molecular weight of from 100 to600 g/mole c) Propylene glycol  5.0-15.0 d) At least one non-ionicethylene  1.0-10.0 oxide/propylene oxide (EO/PO) block copolymer withweight average molecular weight (Mw) from 10,000 to 15,000 e)polyoxyethylene (20) sorbitan 0.5-5.0 monolaurate and/or polyoxyethylene(20) sorbitan monooleate f) Stabilizer 0.05-0.5  Other optionaladditives <20 Water Balance to 100.0%


2. The pharmaceutical composition as claimed in claim 1, which comprisesan aqueous solution having a pH from 5 to 7.5 comprising: ComponentAmount (wt %) Loratadine or a pharmaceutically 0.02-0.1  acceptable saltthereof At least one polyethylene glycol with a  5.0-15.0 molecularweight of from 100 to 600 g/mole Propylene glycol (co-solvent)  5.0-15.0At least one non-ionic EO/PO block  1.0-10.0 copolymer with weightaverage molecular weight (Mw) from 10,000 to 15,000 polyoxyethylene (20)sorbitan 0.5-5.0 monolaurate and/or polyoxyethylene (20) sorbitanmonooleate Stabilizer 0.05-0.5  Other optional additives <20 WaterBalance to 100.0%


3. The pharmaceutical composition as claimed in claim 2, which comprisesan aqueous solution having a pH from 5 to 7 consisting of: ComponentAmount (wt %) Loratadine or a pharmaceutically 0.06 acceptable saltthereof PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/POblock 5.0 copolymer with weight average molecular weight (Mw) of about12,500 Polysorbate 80 1.8 Na₂EDTA 0.1 Water Balance to 100.0%


4. The pharmaceutical composition as claimed in claim 1, which comprisesan aqueous solution having a pH from 5 to 7.5 comprising: ComponentAmount (wt %) Desloratadine or a pharmaceutically 0.02-0.1  acceptablesalt thereof At least one polyethylene glycol with a  5.0-15.0 molecularweight of from 100 to 600 g/mole Propylene glycol  5.0-15.0 At least onenon-ionic EO/PO block  1.0-10.0 copolymer with weight average molecularweight (Mw) from 10,000 to 15,000 polyoxyethylene (20) sorbitan 0.5-5.0monolaurate and/or polyoxyethylene (20) sorbitan monooleate Stabilizer0.05-0.5  Other optional additives <20 Water Balance to 100.0%


5. The pharmaceutical composition as claimed in claim 4, which comprisesan aqueous solution having a pH from 5 to 7 consisting of: ComponentAmount (wt %) Desloratadine or a pharmaceutically 0.6 acceptable saltthereof PEG 400 10.0 Propylene glycol 10.0 At least one non-ionic EO/POblock 5.0 copolymer with weight average molecular weight (Mw) of about12,500 Polysorbate 80 1.8 Na₂EDTA 0.1 Water Balance to 100.0%


6. A method for reducing histamine production wherein said methodcomprises nasally administering, to a subject in need of reducedhistamine production, a pharmaceutical composition of claim
 1. 7. Themethod, according to claim 6, wherein said composition is an aqueoussolution that consists of: a) an antihistamine in an amount between0.02% and 0.1% of the total weight of the composition (wt %), theantihistamine being selected from the group consisting of loratadine,desloratadine, and pharmaceutically acceptable salts thereof; b)polyethylene glycol with a molecular weight between 100 to 600 g/mole inan amount from 5.0 to 15.0 wt %; c) a propylene glycol, in an amountfrom 5.0 to 15.0 wt % ; d) a non-ionic block copolymer, wherein theblock copolymer is an ethylene oxide and propylene oxide blockcopolymer, and wherein the block copolymer is present in an amount from1.0 to 10.0 wt %; and e) a polyoxyethylene sorbitan monolaurate and/ormonooleate, wherein the polyoxyethylene sorbitan monolaurate and/ormonooleate is present in an amount from 0.5 to
 5. 0 wt % and wherein thecomposition is in an aqueous solution having a pH of from 5 to 7.5.
 8. Amethod for relieving allergy symptoms wherein said method comprisesnasally administering, to a subject in need of such relief, apharmaceutical composition of claim
 1. 9. The method, according to claim8, wherein said composition is an aqueous solution that consists of: a)an antihistamine in an amount between 0.02% and 0.1% of the total weightof the composition (wt %), the antihistamine being selected from thegroup consisting of loratadine, desloratadine, and pharmaceuticallyacceptable salts thereof; b) polyethylene glycol with a molecular weightbetween 100 to 600 g/mole in an amount from 5.0 to 15.0 wt %; c) apropylene glycol, in an amount from 5.0 to 15.0 wt % ; d) a non-ionicblock copolymer, wherein the block copolymer is an ethylene oxide andpropylene oxide block copolymer, and wherein the block copolymer ispresent in an amount from 1.0 to 10.0 wt %; and e) a polyoxyethylenesorbitan monolaurate and/or monooleate, wherein the polyoxyethylenesorbitan monolaurate and/or monooleate is present in an amount from 0.5to 5.0 wt % and wherein the composition is in an aqueous solution havinga pH of from 5 to 7.5.